CZ20012335A3 - Process for preparing 5-cyanophthalide - Google Patents

Abstract

A method for the preparation of 5-cyanophthalide in which 5-carboxyphthalide is converted to the corresponding amide of Formula (IV) in which R is hydrogen or C1-6 alkyl, which is then reacted with a dehydrating agent thereby obtaining 5-cyanophthalide. The conversion of 5-carboxyphthalide to the corresponding amide of Formula (IV) may be carried out via the corresponding C1-6 alkyl or phenyl ester or the acid chloride, which is converted to the amide of Formula (IV) by amidation with ammonia or a C1-6 alkylamine. By the process 5-Cyanophtalide, an important intermediate used in the preparation of the antidepressant drug citalopram, is prepared in high yields by a convenient, cost effective procedure.

Description

A process for the preparation of 5-cyanophthalide wherein the 5-carboxyphthalide is converted to the corresponding amide of formula IV wherein R is hydrogen or C 1-6. _The alkyl is then reacted with a dehydrating agent to give 5-cyanophthalide. The conversion of the 5-carboxyphthalide to the corresponding amide of formula IV can be carried out via the corresponding C 1-6. _An alkyl or phenyl ester or acid chloride which is converted to the amide of formula IV by amidation with ammonia or C1-6 alkylamine. In this way, 5-cyanophthalide, an important intermediate used in the manufacture of the antidepressant drug citalopram, is prepared with high yields in a convenient, inexpensive manner.

CZ 2001 - 2335 A3

(IV) o

τν iooi - mr

5-Cyanophthalide

Technical field

The present invention relates to a novel process for the preparation of 5-cyanophthalide which is an intermediate used in the manufacture of the well-known antidepressant drug citalopram, or 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro- Of 5-isobenzofuran-carbonitrile.

BACKGROUND OF THE INVENTION

Citalopram is a well known antidepressant drug that has been on the market for several years and has the following structure:

It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor and thus has antidepressant effects. The antidepressant activity of this compound has been described in several publications, for example, J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.

Citalopram is produced as described in U.S. Pat.

4,650,884, according to which two successive reactions are carried out on 5-cyanophthalide

-2 ··················································· · ·· ·· ·· ···

Grignard reactions, i.e. with 4-fluorophenylmagnesium halide and N, N-dimethylaminopropylmagnesium halide, and ring closure of the obtained compound of formula

dehydration with strong sulfuric acid.

Enantiomers of citalopram can be prepared as described in U.S. Pat. No. 4,943,590, i.e. by separating the enantiomers of the intermediate of formula II and performing enantioselective ring closure to obtain the desired enantiomers.

Thus, 5-cyanophthalide is an important intermediate for the production of citalopram and it is important to produce this substance in the required quality and in a manner which is advantageous from a production point of view and is not expensive.

The process for producing 5-cyanophthalide has been previously described in Bull. Soc. Sci. Bretagne, 26, 1951, 35 and Left and Stephen, J. Chem. Soc., 1931, 867. In this way, 5-aminophthalide is converted to the corresponding 5-cyanophthalide by diazotization followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide by a two-step reduction route.

The synthesis of certain alkyl and phenyinitriles from acid chlorides is described in Tetrahedron Letters, 1982, 23, 14, 1505-1508 and Tetrahedron 1998, 54, 9281.

• · · · · · · · · · · · ·

Although many other methods have failed, it has been found that 5-cyanophthalide can be prepared in a convenient, inexpensive way from 5-carboxyphthalide in high yields.

SUMMARY OF THE INVENTION

Thus, the present invention provides a novel process for the preparation of 5-cyanophthalide from 5-carboxyphthalide, comprising the following steps:.

a) the 5-carboxyphthalide is converted to an amide of formula IV of formula III of formula IV wherein R is a hydrogen atom or a C _1-6 alkyl, and

b) the amide of formula IV is reacted with a dehydrating agent to give a 5-cyanophthalide of formula

The conversion of 5-carboxyphthalide to an amide of formula IV can be carried out via an ester of formula VI or an acid chloride of formula VII or via an ester and an acid chloride of:

wherein R 1 is alkyl or phenyl. The acid chloride is conveniently obtained by reacting 5-carboxyphthalide with POCl ₃ , PCl ₅ or SOCl ₂ in a pure state or in a suitable solvent such as toluene or toluene containing a catalytic amount of Ν, Ν-dimethylformamide. The ester is obtained by reacting the 5-carboxyphthalide with an alcohol R-10, where R 1 is as defined above in the presence of an acid, preferably a mineral acid or a Lewis acid such as HCl, H ₂ SO ₄ , POCl ₃ , PCl ₅ or SOCl ₂ . Alternatively, the ester can be obtained from the acid chloride by reaction with an alcohol. The ester of formula VI or the acid chloride of formula VII is then converted to the amide of formula IV by amidation with ammonia or C 1. ₅

an alkylamine, preferably t-butylamine.

Within the scope of the specification and claims, C _1-6 alkyl is used to denote a branched or unbranched alkyl group containing from 1 to 6 carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 225-methyl-1-propyl.

The dehydrating agent used in step b) may be any suitable dehydrating agent, the optimal agent being readily determined by one skilled in the art. Examples of suitable dehydrating agents are SOCl ₂ , POCl 3 and PCl ₅ , preferably SOCl ₂ .

- 5 * · · · Φ · · 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 ··

The reaction in step b) is carried out with the substances themselves or in a suitable solvent such as toluene, sulfolane or suitably acetonitrile. When the reaction is carried out in a solvent, 1.0 to 1.5, preferably 1.0 to 1.2 equivalents of dehydrating agent is used per equivalent of the amide of formula V. In addition, when a solvent is used, a catalytic amount of N, N-dimethylformamide may be required, especially when SOCl 2 is used as the dehydrating agent. Preferably toluene is used as the solvent, if necessary in the presence of a catalytic amount of N, N-dimethylformamide.

The reaction in step b) is carried out at an elevated temperature, preferably at the reflux temperature of the solvent.

The reaction time is not critical and can be readily determined by one skilled in the art.

The 5-cyanophthalide can be isolated by a suitable method, for example by adding water, filtering and washing the crystals. Further purification can be accomplished by recrystallization if necessary.

In a preferred embodiment of the process of the invention, R in formula IV is hydrogen or t-butyl. When the reaction of step a) is carried out via an ester, the R 1 group is preferably methyl or ethyl.

In a particularly preferred embodiment of the invention, the 5-carboxyphthalide of formula III is reacted with an alcohol R 1 OH, preferably ethanol, in the presence of POCl ₃ to give the corresponding ester of formula VI, which then reacts with ammonia to give 5-carbamoylphthalide a catalytic amount of N, N-dimethylformamide.

Surprisingly, there is essentially no reaction on the lactone ring. Thus, the process of the invention yields 5-cyanophthalide in high yield, and the process is more convenient than known processes and utilizes more convenient and cheaper reagents and reaction conditions.

-6 * * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

The 5-carboxyphthalide used as starting material can be obtained by the methods described in U.S. Pat. No. 3,607,884 or German patent no. 2630927, i.e. by reacting a concentrated solution of teraftalic acid with formaldehyde in liquid SO ₃ , or by electrochemical 5 hydrogenation of trimellitic acid.

DETAILED DESCRIPTION OF THE INVENTION.

The invention will now be illustrated by the following examples.

Example 1

Production of 5-cyanophthalide

5-Chlorocarbonylphthalide

5-Carboxyphthalide (53 g, 0.3 mol) was suspended with toluene (200 mL) and thionyl chloride (44 g, 0.6 mol). N, N-dimethylformamide (DMF) (1 mL) was added and the mixture was heated to reflux for 15 h. The mixture was cooled to room temperature and n-heptane (200 mL) was added. The formed crystals were collected and washed with heptane (100 mL). Yield 52 g, 88%. DSC rise: 131 ° C. ¹ H NMR (CDCl 3, 500 MHz): 5.47 (2H, s), 8.06 (1H, d, J = 7.5Hz), 8.28 (1H, d, J = 7.5Hz) 8.3 (1H, s). ¹³ C NMR (CDCl ₃ , 20 125 125 MHz): 69.4, 125.1, 126.1, 131.1, 131.6, 137.8, 146.6, 167.4, 169.0.

5-tert-Butylcarbamylphthalide

Method A):

5-Carboxyphthalide (36 g, 0.2 mol) was suspended in thionyl chloride (100 mL). DMF (1.5 mL) was added and the mixture was refluxed for 1 h. Toluene (200 mL) was added and the solvents were evaporated in vacuo. The residue was dissolved in tetrahydrofuran (THF) (200 mL) and added to a solution of tert-butylamine (31 g, 0.42 mol) in THF (200 mL) at 5 ° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice water (400 mL) and the precipitated crystals were filtered off. The crystals were washed with water (100 mL). Yield: 41 g, 87%. DSC rise: 189.5 ° C.

Method B):

A solution of 5-chlorocarbonylphthalide (39 g, 0.2 mol) in THF (200 mL) was added to a solution of tert-butylamine (19 g, 0.25 mol) and triethylamine (26 g, 0.25 mol) in THF (200 mL). ml) at room temperature. The mixture was stirred for 1 h. The reaction mixture was then poured into ice water (500 mL). The formed crystalline material was separated and washed with water (100 mL). Yield 42.5 g, 91%. DSC rise: 192 ° C. Purity: 99.5% (HPLC, peak area calculation). ¹ H NMR (DMSO-d 6, 500 MHz): 1.4 (9H, s),

5.46 (2H, s), 7.88 (1H, d, J = 7.5Hz), 7.95 (1H, d, J = 7.5Hz), 8.04 (1H, s). ¹³ C NMR (DMSO-d 6, 125 MHz): 28.5, 51.2, 70.0, 122.0, 124.6, 126.6, 128.2, 141.3, 147.2, 165, 5, 170.1.

5-Ethoxycarbonylphthalide

Method A):

5-Carboxyphthalide (37 g, 0.2 mol) was suspended in ethanol (400 mL). POCl 3 (10 g, 0.07 mol) was added dropwise and the reaction mixture was heated to reflux for 5 hours. After cooling to ambient temperature, the title compound crystallized. The crystals were filtered off and washed with ethanol (50 ml). Yield: 35 g, 87%. DSC rise: 151 ° C.

¹ H NMR (DMSO-d 6, 250 MHz): 1.36 (3H, t, J = 7Hz), 4.38 (2H, q, J = 7Hz), 5.48 (2H, s), 7 95 (1H, d, J = 7.5Hz); 8.12 (1H, d, J =

7.5 Hz). ¹³ C NMR (DMSO-d ₆ , 62.5 MHz): 14.5, 61.5, 70.1, 124.0, 125.2, 128.8, 129.6, 134.8, 147.6 , 164.9, 169.8.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Φ ·

- 8 · - * ············

Method Β):

5-Chlorocarbonylphthalide (39 g, 0.2 mol) was suspended in ethanol (200 mL). The mixture was refluxed for 15 min. After cooling, the formed crystalline material was filtered off and washed with ethanol (50 ml). Yield: 36 g, 88%. DSC rise: 151 ° C.

5-Carbamylphthalide

Method A):

5-Ethoxycarbonylphthalide (41 g, 0.2 mol) was suspended in ammonia (10M solution in methanol, 200 mL) in a pressurized reactor. The reaction temperature was maintained at 80 ° C for 20 hours. After cooling, the reaction mixture was poured into ice (250 g) and the pH was adjusted to pH = 1 using concentrated hydrochloric acid. The mixture was stirred for 2 h. The formed crystals were filtered and washed with water (4 x 100 mL) and dried in vacuo. Yield: 33 g, 93%. DSC rise: 237 ° C. ¹ H NMR (DMSO-d 6, 250 MHz): 5.47 (2H, s), 7.65 (1H, s (NH)), 7.92 (1H, d, J = 7.5 Hz), 8 06 (1H, d, J = 7.5Hz), 8.14 (1H, s), 8.22 (1H, s (NH)). ¹³ C NMR (DMSO-d 6, 62.5 MHz): 70.0, 122.2, 124.9, 127.2, 128.2, 139.7, 147.4, 167.1, 170.1.

Method B):

5-Chlorocarbonylphthalide (20 g, 0.1 mol) was dissolved in THF (100 mL) and added to ammonium hydroxide (50 mL) in ice water (300 mL). The mixture was stirred for 30 min and the precipitated crystals were filtered off. The crystals were washed with water (100 mL) and dried in vacuo. Yield: 17.1 g, 97%. DSC rise: 237 ° C.

9 ·· ··· «·· φ · · 9 · · 9 999 g 99 9 99 · 9 99 · 9 ·» ·

5-Cyanophthalide

Method A):

Dry 5-carbamylphthalide (36 g, 0.2 mol) was suspended in toluene (600 mL) and thionyl chloride (36 g, 0.3 mol) was added. DMF (2 mL) was added. The reaction mixture was heated at 75 ° C for 6 hours. Toluene (100 mL) was removed by distillation and the remaining solution was cooled to ambient temperature. The formed crystals were filtered and washed with toluene (150 mL) and water (100 mL). The product was recrystallized from toluene. Yield: 22 g, 80%. DSC rise: 203 ° C.

Method B):

Tert-butylcarbamylphthalide (23.3 g, 0.1 mol) was suspended in thionyl chloride (100 mL). The mixture was heated to reflux for 30 min. Toluene (100 mL) was added and the solvents were removed in vacuo. The title product was crystallized from acetic acid or toluene.

Yield 15.5 g, 93% from toluene. DSC rise: 203 ° C. Purity: 98% (HPLC, peak area calculation).

Represented by:

- 10,

PATENT CLAIMS

Claims (12)

1. A process for the production of 5-cyanophthalide comprising the steps of: 5 a) 5-Carboxyphthalide is converted to the amide of formula IV of formula III NHR wherein R is hydrogen or C 1-6 alkyl, and b) reacting the amide of formula IV with a dehydrating agent to give 5-cyanophthalide Process according to claim 1, characterized in that the conversion of the 5-carboxyphthalide to the amide of the formula IV is carried out via an ester of the formula VI: Formula VI wherein R 1 is C 1-6 alkyl or phenyl, by reacting 5-carboxyphthalide with an alcohol R 10 OH in the presence of an acid followed by amidation of the ester of Formula VI with ammonia or C 1-6 alkylamine. Process according to claim 1, characterized in that the conversion of the 5-carboxyphthalide to the amide of the formula IV is carried out via the acid chloride of the formula VII: 20 by reacting 5-carboxyphthalide with POCl 3, PCl 5 or SOCl 2 followed by amidation of the acid chloride of formula VII with ammonia or C 1. ₆ alkylamine. Process according to claim 1, characterized in that the conversion of the 5-carboxyphthalide to the amide of the formula IV is carried out via the acid chloride of the formula VII and the ester of the formula VI: • · φ - 12 J. φ VI φ · vzor vzor φ φ φ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ Φ ₆ alkyl or phenyl, by reaction of 5-carboxyphthalide with POCl 3, PCl 5 or SOCl ₂ , by reaction of the formed acid chloride of formula 10 VII with an alcohol R-10, and amidating the ester of the formula VI with ammonia or C 1-6 alkylamine. Process according to claim 2, characterized in that the acid used is a mineral acid or a Lewis acid 15 such as HCl, H ₂ SO ₄ , POCl ₃ , PCl ₅ , SOCl ₂ . A process according to claim 2, 4 or 5 wherein R 1 is methyl or ethyl. 20 May Method according to one of claims 1 to 6, characterized in that SOCl 2, POCl 3 or PCl 5, preferably SOCl 2, is used as the dehydrating agent in step b). Method according to one of Claims 1 to 7, characterized by: The reaction in step b) is carried out with the substances themselves or in a suitable solvent such as toluene, sulfolane or acetonitrile, preferably toluene. Process according to claim 8, characterized in that SOCl ₂ is used as the dehydrating agent in step b) and the reaction is carried out in toluene containing a catalytic amount 5 N, N-dimethylformamide. The process according to any one of claims 1 to 9, wherein R is hydrogen or tert-butyl. io Process according to claim 2, characterized in that the 5-carboxyphthalide of formula III is reacted with an alcohol R 10 OH, preferably ethanol or methanol, in the presence of POCl 3 to obtain an ester of formula VI which is then reacted with ammonia to give 5-carbamoylphthalide that reacts with 15 SOCl 2 to give 5-cyanophthalide. A process according to claim 11, wherein the reaction of 5-carboxyphthalide III with ethanol in the presence of POCl 3 is carried out to obtain the ethyl ester VI, which is then reacted with ammonia in methanol to give 5carbamoylphthalide which reacts with SOCl 2 to give 5cyanophthalide . Represented by: